Anti-inflammatory compounds

ABSTRACT

4-(Thien-2-oyl- and thien-3-oylphenyl)pentan-2-ones and 4-(thien-2-oyl- and thien-3-oylphenyl)butan-2-ones, the corresponding pentan-2-ols and butan-2-ols, and esters of the latter alkanols are anti-inflammatory agents. The compounds, of which 4-[4-(2-thienoyl)phenyl]pentan-2-one is a representative embodiment, can be prepared by acylation of the corresponding 4-phenylpentan-2-one, 4-phenylbutan-2-one, or an ester of the corresponding pentan-2-ol or butan-2-ol, with a thienylcarboxylic acid, or by acylation of a 4-(4-carboxyphenyl)pentan-2-one, 4-(4-carboxyphenyl)butan-2-one or an ester of the corresponding pentan-2-ol or butan-2-ol with thiophene, optionally in either case with subsequent reduction of the resultant alkanone and with optional esterification of the resultant alkanol.

CROSS-REFERENCE

This is a continuation of Ser. No. 815,645 filed July 14, 1977, nowabandoned.

The present invention relates to thiophene derivatives, to theirpreparation and to compositions containing them.

Acidic anti-inflammatory agents such as suprofen tend to suffer fromgastro-intestinal side effects. Furthermore such compounds requiresomewhat long synthetic sequences for production. Suprofen has theformula (O): ##STR1## and has been described in Arzneim. Forschung, 25(11), 1975 and U.K. Pat. No. 1,446,239. A group of non-acidanti-inflammatory agents has now been discovered which show a reducedpropensity to cause side effects such as gastro-intestinal irritancy andwhich are prepared by a conveniently short synthetic sequence.

Accordingly the present invention provides the compounds of the formula(I): ##STR2## wherein A is a --CHRCH₂ -- or --CR═CH-- group where R is ahydrogen atom or a methyl group and B is a CO, CHOH or CHOCOR¹ groupwhere R¹ is a group such that HO.COR¹ is a pharmaceutically acceptableorganic acid of up to 12 carbon atoms.

Suitably R¹ is a hydrocarbon group such as an alkyl, alkenyl, aryl,aralkyl or like group optionally substituted by alkoxyl, carboxyl,carboxamide, hydroxyl, acyloxy, amino, or salted amino, acylamino,alkylamino, dialkylamino or the like. More suitably R¹ is such a groupwhich contains up to 8 carbon atoms.

Preferred groups R¹ include the phenyl group, alkyl groups of 1-4 carbonatoms, alkyl groups of 1-4 carbon atoms substituted by a phenyl group,or one of these groups substituted by hydroxyl, acetoxyl, methoxyl,acetamido, amino, salted amino, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino,carboxyl or the like groups.

Particularly suitable groups R¹ include alkyl groups of 1-4 carbon atomssuch as the methyl, ethyl, and n-propyl groups. Other groups include thephenyl, benzyl, phenylethyl, acetoxymethyl, methoxymethyl,hydroxymethyl, aminomethyl, 2-acetoxyphenyl, 4-methoxyphenyl,3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl or the like groups.

Aptly B is a CO, CHOH or CHOCOR" group where R" is an alkyl group of 1-4carbon atoms.

Most suitably the phenyl moiety is 1-4 disubstituted as such compoundsare particularly conveniently synthesised as hereinafter described.

Thus particularly suitable compounds of the formula (I) include those ofthe formulae (II) and (III): ##STR3## wherein A and B are as defined inrelation to formula (I).

Favoured values for the group B in the compounds of the formulae (I),(II) and (III) include the CO and CHOH groups.

A particularly favoured value for the group A in the compounds of theformulae (I), (II) and (III) includes the --CHCH₃ CH₂ -- group.

Thus further particularly suitable compounds of this invention includethose of the formula (IV) and (V): ##STR4## wherein B is as defined inrelation to formula (I).

More suitably B the compounds of the formulae (IV) and (V) is a CO, CHOHor CHOCOR¹ group.

Yet more favourably B in the compounds of the formulae (IV) and (V) is aCO or CHOH group.

Preferably B in the compounds of the formulae (IV) and (V) is a COgroup.

Those compounds of this invention which contain a chiral center may bein the form of R or S isomers or mixtures thereof such as the R,S-- formabout that center.

Those compounds in which the group A is a CHCH₃ CH₂ group more suitablyhave the S-- or R,S-- conformation about the chiral center as the S--compounds are more potent anti-inflammatory agents than thecorresponding R-- compounds.

The present invention also provides a pharmaceutical composition whichcomprises a compound of the formula (I) and a pharmaceuticallyacceptable carrier.

Normally the composition of this invention is adapted for oraladministration.

The composition may be presented as any conventional dosage form such astablets, capsules, sachets of reconstitutable powder or the like. Mostsuitably the composition is in the form of a unit dose containing 20-600mg of a compound of the invention, e.g. 50 to 400 mg. Such compositionsmay be administered once or more times per day so that the total dailydose for a 70 kg adult will be in the order of 40-1200 mg, for example100-600 mg.

The compositions may be prepared in conventional manner by mixing,filling, tabletting and the like and the compositions may containconventional excipients such as lubricants, disintegrants, binders,fillers, colouring agents, flavours and the like. The compositions maybe formulated in known manner as described for such knownanti-inflammatory agents as indomethacin, naproxen, ketoprofen,phenylbutazone or the like.

The present invention provides a process for the preparation of thecompounds of the formula (I) which process comprises:

(a) the acylation of a compound of the formula (VI): ##STR5## wherein B¹is a group within B as defined in relation to formula (I) but excludingthe CHOH group with an acylating derivative of a thienylcarboxylic acid;and thereafter if desired reducing the side chain carboxyl group of acompound wherein B¹ is a CO group:

(b) the acylation of thiophene with an acylating derivative of the acidof the formula (VII): ##STR6## wherein B¹ is as defined in relation toformula (VI) and thereafter if desired reducing the side chain carboxylgroup of a compound wherein B¹ is a CO group and thereafter if desiredacylating the resulting hydroxyl group with an acylating derivative of alower alkyl carboxylic acid.

Normally the aromatic acylation is brought about under conventionalFriedel Craft acylating conditions, for example by using an acidchloride in the presence of a Lewis acid such as aluminium chloride orantimony chloride in an inert solvent such as carbon disulphide ormethylene chloride.

Most suitably the reaction is performed upon a compound of the formula(VI) or (VII) wherein B¹ is a CO group.

Those compounds of the invention wherein B is a CHOH group may beprepared by reducing the corresponding compound wherein B is a CO groupusing sodium borohydride in a solvent such as ethanol or by usinglithium aluminium hydride in a solvent such as diethyl ether followed byregeneration of the diaryl ketone using manganese dioxide in an inertsolvent such as benzene.

Process (a) is generally used to provide the parasubstituted compoundsof the formulae (II) and (III). Process (b) is generally used to providethe 2-thienyl derivatives within formula (I). It will be appreciatedthat such short processes leading to compounds of the invention are veryconvenient.

The following Examples illustrate the invention:

EXAMPLE 1 4-[4'-(2'-Thienoyl)-phenyl]-pentan-2-one

To a stirred mixture of aluminium chloride (39 g) in carbon disulphide(150 ml) at 0° C. was added dropwise over 1 hour a mixture of4-phenyl-pentan-2-one (15 g) and thienyl-2-carboxylic acid chloride(12.8 g). After the resulting dark solution had been left at roomtemperature overnight, the top layer was decanted off and the lower,more viscous layer was poured carefully onto cold water (about 500 ml).The crude product was extracted into chloroform (3×150 ml), washed withdilute sodium bicarbonate solution (200 ml), dried (Na₂ SO₄),concentrated by evaporation under reduced pressure and distilled (b.p.190°/0.08 mm). The residual oil crystallised from ethyl acetate/petrolto give pure 4-[4'-(2'-thienoyl)-phenyl]-pentan-2-one, m.p. 60°-1° C.

EXAMPLE 2 4-[4'-(2'-Thienoyl)-phenyl]-butan-2-one

The procedure of Example 1 was used except that benzyl acetone was usedin place of the 4-phenylpentan-2-one. The initially produced somewhatcrude product was crystallised from carbon tetrachloride/hexane to givepure 4-[4'-(2'-thienoyl)-phenyl]-butan-2-one, m.p. 77°-78° C.

EXAMPLE 3 4-[4'-(3'-Thienoyl)-phenyl]-butan-2-one

To a stirred mixture of 3-thienoyl chloride (3.0 g) and benzyl acetone(3.0 g) at 0° C. in methylene chloride (50 ml) was added dropwise over30 minutes antimony pentachloride (3.3 ml). After the reaction mixturehad been left at 0° C. for a further 30 minutes and then at roomtemperature for 3 hours, more antimony pentachloride (3.3 ml) was addeddropwise and then the amber solution was left for 1 hour at roomtemperature before being poured onto cold. dilute aqueous hydrochloricacid (about 50-60 ml). The aqueous layer was separated, washed withchloroform (2×100 ml) and then the combined organic layer was washedsuccessively with dilute aqueous sodium bicarbonate (about 100 ml) andwater (about 100 ml), dried (Na₂ SO₄) and concentrated by evaporationunder reduced pressure. The crude oil (4.4 g) was chromatographed onsilica using ether/40°-60° petrol as eluant to afford a pale yellow oilwhich slowly solidified on standing (1.1 g) to a pale amber colouredsolid. This material was rechromatographed to yield a colourless solid(400 mg). Recrystallisation of this solid from ether/pentane gaveanalytically pure 4-[4'-(3'-thienoyl)-phenyl]-butan-2-one, m.p. 63°-4°C.

EXAMPLE 4 S-4-[4'-(2'-Thienoyl)-phenyl]-pentan-2-one

To a stirred mixture of aluminium trichloride (24.45 g) in carbondisulphide (95 ml) at 0° C. was added dropwise over 1 hour a mixture ofS-4-phenyl-pentan-2-one (9.4 g) and thienyl-2-carboxylic acid chloride(8.02 g). After the resulting dark solution had been stirred for 24hours at room temperature, the top layer was decanted off and the lowerviscous layer was poured carfully into ice cold dilute hydrochloric acid(about 300 ml). The crude product was extracted into chloroform (3×100ml), washed with dilute sodium bicarbonate solution (120 ml), dried (Na₂SO₄), concentrated by evaporation under reduced pressure and distilledat 176°-178°/0.08 mm to yield a dark oil (9 g). This was chromatographedon alumina using gradient elution with ether and hexane as eluant. Theresultant analytically pure S-4-[4'-(2'-thienoyl)-phenyl]-pentan-2-one(5.9 g) had an optical rotation α_(D) ¹⁸.5 =-76.53 (benzene).

S-4-phenyl-pentan-2-one was prepared from S-3-phenylbutyric acid([α]_(D) ¹⁸ =-60.05° in benzene by the method of H. Rupe, Annelen 1901,369, 311) via its acid chloride by the following method.

Methyl lithium (100 ml of a 2 M solution in ether: 0.2 mole) was addeddropwise at 0° C. to cuprous iodide (19 g: 0.1 mole) in dry ether (60ml) under nitrogen. The solution was then stirred for 10 minutes at 0°C., cooled to -65° and S-3-phenyl-butyroyl chloride (from 4.93 g (0.03mole) of S-3-phenyl-butyric acid and 10 ml of oxalyl chloride) in dryether (60 ml) was added slowly. After 15 minutes at -65°, methanol (33ml) was added dropwise and when the resulting mixture reached -30° C.dilute hydrochloric acid was used to neutralise the solution. Afterfiltration through Kieselguhr, the ether layer was separated and theaqueous layer further extracted with ether. The combined organic layerwas then washed with water, dilute aqueous sodium bicarbonate, dried(Na₂ SO₄), concentrated and distilled to afford pureS-4-phenyl-pentan-2-one (4.1 g), b.p. 110°/11 mm: [α]_(D) ¹⁸ =-74.5°(benzene).

EXAMPLE 5 R-4-[4'-(2'-Thienoyl)-phenyl]-pentan-2-one

This was prepared following the procedure of Example 4 except thatR-4-phenyl-pentan-2-one was used as starting material. PureR-4-[4'-(2'-thienoyl)-phenyl]-pentan-2-one, was obtained, [α]_(D) ¹⁸.5=+72.08 (benzene).

R-4-phenyl-pentan-2-one was prepared from R-3-phenylbutyric acid([α]_(D) ²³.3 =57.12° in benzene by the method of A. Weidler and G.Bergson, Acta. Chem. Scand., 1964, 18, 1484) via its acid chloride asfollows.

A mixture of ethanol (1.7 ml) and carbon tetrachloride (0.34 ml) wasadded dropwise to dry magnesium (5.33 g). After the exothermic reactionhad subsided, ether (35 ml) was added cautiously. Diethyl malonate(35.56 g), ether (35 ml) and ethanol (17.5 ml) were added at such a rateas to maintain reflux which was then continued overnight. To theresulting stirred solution was added dropwise R-3-phenyl-butyroylchloride (from 28.29 g of R-3-phenyl-butyric acid and oxalyl chloride)in ether (100 ml) to maintain reflux which was then continued for afurther hour after addition. After acidification with dilutehydrochloric acid the aqueous layer was extracted with ether and thenthe combined organic layer washed with water and concentrated. Treatmentof the resulting crude oil with dimethyl sulphoxide (45 ml) and water (7ml) at 140° for 5 hours gave, after work-up in the usual manner, pureR-4-phenyl-pentan-2-one (24.7 g), b.p. 110°/11 mm: [α]_(D) ²⁰.0 =+73.0(benzene).

EXAMPLE 6 Composition

Hard gelatin capsules may each be filled with a mixture of the compoundof Example 1 (100 mg) and magnesium stearate (5 mg).

EXAMPLE 7 Pharmacology

The compound of Example 1 showed good activity on the reduction ofcarrageenin induced oedema test at 10 mg/kg. At 10 mg/kg the compound ofExample 1 did not cause severe irritation to the stomachs of the testanimals. When tested on the phenylquinone induced writhing test thecompound of Example 1 had an ED₅₀ of 4.2 mg/kg (c.f. 0.78 for suprofen).

The compound of Example 4 produced a 47% inhibition of oedema in thecarrageenin test at 125 mg/kg and 52% at 25 mg/kg. On this test thecompound of Example 5 produced a 36% inhibition at 125 mg/kg but only14% at 25 mg/kg.

What we claim is:
 1. A compound of the formula: ##STR7## wherein A is--CHRCH₂ -- or --CR═CH-- in which R is hydrogen or methyl and B is CO,CHOH or CHOCOR¹ wherein R¹ is phenyl, alkyl of 1 to 4 carbon atoms,alkyl of 1 to 4 carbon atoms substituted by phenyl, or phenyl, alkyl of1 to 4 carbon atoms, or alkyl of 1 to 4 carbon atoms substituted byphenyl, said phenyl, alkyl or phenyl substituted alkyl being substitutedby a member selected from the group consisting of hydroxyl, acetoxyl,methoxyl, acetamido, amino or a nontoxic salt thereof, alkylamino of 1to 4 carbon atoms in the alky moiety, dialkylamino of 1 to 4 carbonatoms in each alkyl moiety and carboxyl.
 2. A compound according toclaim 1 which has the formula: ##STR8## wherein A is --CHRCH₂ -- or--CR═CH-- in which R is hydrogen or methyl and B is CO, CHOH or CHOCOR"where R" is alkyl of 1 to 4 carbon atoms.
 3. A compound according toclaim 1 wherein B is CO or CHOH.
 4. A compound according to claim 1wherein A is --CHCH₃ CH₂ --.
 5. A compound according to claim 1 whichhas the formula: ##STR9## wherein B is CO, CHOH or CHOCOR" wherein R" isalkyl of 1 to 4 carbon atoms.
 6. A compound according to claim 5 whereinB is CO or CHOH.
 7. A compound according to claim 4 wherein B is CO. 8.A compound according to claim 1 which has a chiral centre which is inR--, S-- or RS-- form.
 9. A compound according to claim 1 in which R ismethyl wherein the chiral carbon atom α- to the phenyl ring is in theS-- or SR--form.
 10. The compound according to claim 1 which is4-[4'-(2-thienoyl)-phenyl]-pentan-2-one.
 11. The compound according toclaim 1 which is 4-[4'-(2'-thienoyl)-phenyl]-butan-2-one.
 12. Thecompound according to claim 1 which is4-[4'-(3'-thienoyl)-phenyl]-butan-2-one.
 13. The compound according toclaim 1 which is S-4-[4'-(2'-thienoyl)-phenyl]-pentan-2-one.
 14. Thecompound according to claim 1 which isR-4-[4'-(2-thienoyl)-phenyl]-pentan-2-one.
 15. The compound according toclaim 1 which has a chiral center and is in the form of the R-isomer.16. The compound according to claim 1 which has a chiral center and isin the form of the S-isomer.
 17. A mixture of R and S-isomers of acompound according to claim 1 having a chiral center.
 18. A compoundaccording to claim 1 wherein R¹ is alkyl of 1 to 4 carbon atoms, phenyl,benzyl, phenylethyl, acetoxymethyl, methoxymethyl, hydroxymethyl,aminomethyl, 2-acetoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl or3,4,5-trimethoxyphenyl.
 19. A compound according to claim 1 wherein R¹is methyl, ethyl, n-propyl, phenyl, benzyl, phenylethyl, acetoxymethyl,methoxymethyl, hydroxymethyl, aminomethyl, 2-acetoxyphenyl,4-methoxyphenyl, 3,4,-dimethoxyphenyl or 3,4,5-trimethoxyphenyl.
 20. Acompound according to claim 1 wherein B is CO, CHOH or CHOCOR" whereinR" is alkyl of 1 to 4 carbon atoms.